PROJECT SUMMARY/ABSTRACT This proposal is to evaluate the impact and cost effectiveness of combination HIV prevention interventions on population-level HIV incidence in Botswana, a country with a severe generalized HIV epidemic. Despite a 25% prevalence in adults, Botswana has led Africa in scale-up of several interventions for HIV prevention and treatment. The proposal will use 16 distinct, randomized rural communities to meet combination prevention goals of HIV Testing and Counseling (HTC), adult male circumcision (MC), AntiRetroviral Therapy (ART) for patients with AIDS or CD4 d 250, and Prevention of Mother-to-Child Transmission (PMTCT). Eight control communities (Arm A) and 8 enhanced combination-prevention communities (Arm B) will be compared for HIV incidence, anticipating a reduction of e 50% over the study period for Arm B. A third (Arm C) in Mochudi will provide a step-wedge design with 6 communities to add a 3-drug ART intervention for individuals with high viral-load (high viral load carriers ) along with the enhanced combination prevention interventions used in Arm B, which we anticipate will provide even greater reductions in HIV incidence. All arms will evaluate HIV incidence over the 4-year study. Arms B and C will also include extensive extra activities, such as: community mobilization and education, enhanced HTC, mobile night clinics, linkage with various community organizations, and partner testing; extra testing techniques such as point-of-care CD4 testing to detect a larger fraction of patients who qualify for ART and PMTCT; and earlier ART initiation and enhanced monitoring of the same populations. For ART and PMTCT, we expect our targets to exceed those indicated in the RFA. The Botswana-Harvard Partnership (BHP) is a not-for-profit organization chartered under the laws of Botswana, and is based upon a 15-year official collaboration between Harvard and the Botswana Ministry of Health. In addition to serving as the original source agency to develop the Botswana PEPFAR and the National ART Program, as well as the largest AIDS-related training program in the country, the BHP has conducted scientific studies and extensively published on all the major prevention interventions addressed in the RFA. The BHP also has a large-capacity accredited laboratory that is central in location to the study sites and serves as the national reference lab for HIV/AIDS.